The hypothesis that the pancreatic beta cell is a primary site of pathology in human diabetes mellitus and that the number of functioning beta cells may play a role in the initiation and/or outcome of the disease, has directed our attention to the need for further study of the embryogenesis and natural history of the beta cell and pancreatic islets. This proposal is for support of projects designed to clarify and correlate ultrastructural and functional events within the pancreatic islets of subhuman primates and in laboratory models of induced or spontaneous diabetes mellitus. The resolution of controversial concepts of the regulation of insulin secretion has been hindered heretofore by the unavailability of satisfactory model systems and techniques for studying pancreatic islet cells in vitro and for studying beta cell plasma membranes. This request is therefore also for the support of projects designed to study morphologic and functional events within monolayer cultures of pancreatic islet cells and to elucidate mechanisms of insulin release by means of freeze-etching studies of islets derived from animals with spontaneous diabetes.